Highly efficient and enantioselective cyclization of aromatic imines via directed C-H bond activation

Article abstract of DOI:10.1021/ja0394986

The first highly enantioselective catalytic reaction involving aromatic C-H bond activation is communicated. Enantioselective cyclization of aromatic ketimines containing alkenyl groups tethered at the meta position of an imine directing group has been achieved using 5 mol % [RhCl(coe)₂]₂ and 15 mol % of an (S)-binol-derived phosphoramidite ligand. Selectivities of up to 96% ee and up to quantitative yields were obtained. Moreover, the identified catalyst system enables the intramolecular alkylation reaction to be performed at temperatures 75 °C lower than our previously reported achiral system. The reaction can even be performed at room temperature for one of the optimal substrates. Copyright

Full text of DOI:10.1021/ja0394986

Published on Web 05/22/2004
Highly Efficient and Enantioselective Cyclization of Aromatic Imines via
Directed C-H Bond Activation
Reema K. Thalji, Jonathan A. Ellman,* and Robert G. Bergman*
Center for New Directions in Organic Synthesis,† Department of Chemistry, UniVersity of California-Berkeley,
and Chemical Sciences DiVision, Lawrence Berkeley National Laboratory, Berkeley, California 94720
Received November 8, 2003; E-mail: jellman@uclink.berkeley.edu, bergman@cchem.berkeley.edu
Chart 1
Despite substantial recent research activity in the C-H activation
area,1,2 to our knowledge there is only one report on the catalytic
enantioselective coupling of aromatic C-H bonds with alkenes.3
In that case, only very modest ees were observed. Recently, we
reported on the intramolecular alkylation of aromatic imines in
which the alkene is tethered meta to the imine (eq 1).4 This reaction
exhibits a much broader alkene scope than that obtained in related
systems2 and provides an efficient route to functionalized bicyclic
ring systems that would be difficult to access by other methods.
By allowing the coupling of highly substituted alkenes, this reaction
enables the preparation of branched products bearing stereocenters.
Herein, we communicate our development of an asymmetric variant
of these reactions, leading to the first highly enantioselective
catalytic reaction involving aromatic C-H bond activation. More-
Table 1. Asymmetric Cyclization of Ketimine 17 Using Various
over, the identified catalyst system enables the intramolecular
alkylation reaction to be performed at temperatures 75 °C lower
than our previously reported conditions. Indeed, the reaction can
even be carried out at room temperature for one of the optimal
substrates. This reaction should prove to be especially valuable in
view of the fact that there are no known general methods for
preparing these compounds enantioselectively.
Chiral Monophosphine Ligands
ligand
temp (°C)
time (h)
% yield 18a
%eeb
nd
nd
8 (S)
nd
35 (R)
23 (S)
17 (R)
9 (R)
38 (R)
0
nd
19 (S)
0
1
2
3
4
5
125
125
125
125
75
20
20
20
20
6
5c
tracec
48c
9c
99
56
6
7
100
75
6
20
20
20
20
20
2.5
2.5
2.5
<2
<2
<2
93c
94c
91c
34c
6c
8
9
75
75
We focused our efforts on the chiral monodentate phosphorus
ligands displayed in Chart 1 because chelating phosphines provide
inefficient catalysts for this reaction. Our investigation began by
testing the cyclization of ketimine 17 with rhodium complexes of
each of these ligands (Table 1). Of the phosphines tested (1-6),
the P-N ligands (1, 2, and 4) gave poor conversions; these results
are consistent with the previous observation that chelating ligands
retard the reaction rate. The P-O ligands 3, 5, and 6 gave much
higher conversions, probably due to the fact that oxygen coordinates
more weakly than nitrogen to late transition metal centers. Notably,
rhodium complexes of 5 and 6 both proved to be much more
efficient catalysts than the previously reported achiral Wilkinson’s
catalyst (125 °C, 4 h) but gave only modest ees.
10
11
12
13
14
15
16a
16b
125
125
125
125
125
125
125
125
15c
14c
52c
100
100
99
58 (S)
83 (S)
88 (S)
87 (S)
a Yields based on 1H NMR integration relative to 2,6-dimethoxytoluene
internal standard. b Ees determined after hydrolysis of 18 with 1 N HCl
(aq) using chiral GC or HPLC. Sense of induction is indicated in parentheses.
c Remainder of mass balance is unreacted starting material.
obtained with the (S)-binol-derived phosphoramidites 15, 16a, and
16b.
Phosphite and phosphoramidite ligands are appealing due to the
ease and modularity of their syntheses.5 The (-)-TADDOL-based
phosphites 7-9, the (-)-TADDOL-based phosphonite 10, the (S)-
binol-derived phosphite 11, and phosphoramidites that incorporate
unhindered secondary amines 12-14 all proved to be ineffective
catalysts, giving either poor conversions, poor ees, or both. In
contrast, impressive enantioselectivities and conversions were
Ketimine 17 cyclized quantitatively in the presence of 5 mol %
[RhCl(coe)2]2 and 15 mol % 16a to give 18 in 88% ee within 2 h
at 125 °C. The sense of stereochemical induction is predominantly
determined by the binol backbone of the phosphoramidite ligands;
comparing diastereomers 16a (88% ee, 125 °C) and 16b (87% ee,
125 °C) shows that the stereochemistry of the amino group is
insignificant. The phosphoramidite/Rh ratio in the cyclization of
17 was found to be optimal at 1.5 or 1; higher ratios significantly
slow the reaction rate without affecting enantioselectivity.6 This
† The Center for New Directions in Organic Synthesis is supported by Bristol-
Meyers Squibb as a Sponsoring Member.
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J. AM. CHEM. SOC. 2004, 126, 7192-7193
10.1021/ja0394986 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Cyclization of Aromatic Iminesa,b
the desired product 26 in high yield and with 96% ee (entry 25).
Here again, ligand 16b is a less efficient catalyst but provides an
ee as high as that obtained with diastereomer 16a (entry 28).
The exceptional rates and enantioselectivities observed using the
phosphoramidite ligands6 may be due to their unique binding pro-
perties, which include reduced σ donation to rhodium and enhanced
π acceptor ability compared to phosphines. The enantioselectivities
are presumably due to highly diastereoselective migratory insertion
of the olefin into the Rh-H bond after C-H activation.9
In summary, we have developed a highly enantioselective and
efficient method for the intramolecular imine-directed C-H/olefin
coupling reaction using chiral phosphoramidite ligands. Application
of this methodology to other substrates and to the preparation of
biologically relevant compounds is currently underway.
Acknowledgment. This work was supported by the NIH
GM069559 (to J.A.E.) and the Director and Office of Energy
Research, Office of Basic Energy Sciences, Chemical Sciences
Division, U.S. Department of Energy, under Contract DE-AC03-
76SF00098 (to R.G.B.).
Supporting Information Available: Complete experimental details
and spectral data for all compounds described (PDF, CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
a Reactions performed using 5 mol % [RhCl(coe)2]2 and 15 mol % ligand
in toluene-d8. b Absolute configurations of (S)-22 and (R)-26 were assigned
by chemical derivatization and X-ray structure determination (see Supporting
Information). The absolute configurations of (S)-18, (S)-20, and (R)-24 were
assigned by analogy. c Yields based on 1H NMR integration relative to 2,6-
dimethoxytoluene internal standard. d Ees determined after hydrolysis of
the imine product using chiral GC or HPLC. e Performed using 10 mol %
ligand.
References
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Organomet. Chem. 1999, 3, 47-79. (b) Guari, Y.; Sabo-Etienne, S.;
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633-639.
result suggests that only one ligand is bound to the metal in the
active catalyst.
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F.; Yamada, A.; Chatani, N.; Murai, S. Chem. Lett. 1997, 425-426. (c)
For atropselective alkene coupling to biaryl compounds, see: Kakiuchi,
F.; Le Gendre, P.; Yamada, A.; Ohtaki, H.; Murai, S. Tetrahedron:
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M.; Funakoshi, K.; Sakai, K. Tetrahedron 1991, 47 (27), 4879-4888.
Barnhart, R. W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.;
Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821-1830. (e) For a review
of enantioselective C-H activation via metal-carbenoids, see: Davies,
H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103 (8), 2861-2903. (f)
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Rodewald, S.; Jordan, R. F. J. Am. Chem. Soc. 1994, 116, 4491-4492.
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R. G.; Ellman, J. A. Org. Lett. 2003, 5 (8), 1301-1303.
(5) (a) For TADDOL-derived ligands, see: Alexakis, A.; Burton, J.; Vastra,
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F.; Rosset, S. Eur. J. Org. Chem. 2000, 4011-4027. (b) For binol-derived
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(6) Similar results were observed in Rh-catalyzed hydrogenation using
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Chemtracts: Org. Chem. 1996, 9, 1.
Due to the efficiency of the reaction with ligands 15, 16a, and
16b at 125 °C, we lowered the temperature in hopes of further
enhancing the enantioselectivity (Table 2). Indeed, at 50 °C, the
cyclization of 17 using ligand 16a proceeded with 95% ee and 94%
yield in 9 h (Table 2, entry 4). It is noteworthy that the temperature
is 75 °C lower than that required in our previously optimized study
using Wilkinson’s catalyst.4a Similar increases in ee were obtained
using ligands 15 and 16b, although reaction rates were not as high
(Table 2, entries 2 and 6).
To explore the scope of this enantioselective cyclization reaction,
substrates 19, 21, 23, and 25 were evaluated using the optimal
ligands (Table 2). At 125 °C, complete conversion was observed
within 1 h for each ligand. Upon lowering the temperature to 50
or 75 °C, ligands 16a and 16b consistently provided more efficient
reaction rates than ligand 15, and 16a was slightly more efficient
than 16b. Ligands 16a and 16b also provided higher enantio-
selectivities for all but the sterically encumbered silyl substrate
19 where the least hindered ligand 15 gave the optimal result
(entry 7). Importantly, ketimine 19 is a versatile substrate, as the
SiMe2Ph functionality can be stereospecifically converted into an
OH group using conditions developed by Fleming7 and Tamao8
(eq 2). Styrenyl substrate 21 and indole 23 both cyclized rapidly,
and ligand 16a gave the best conversion and enantioselectivity
(entries 15 and 19, respectively).
(8) Tamao, K. AdV. Silicon Chem. 1996, 3, 1.
(9) This is assuming a mechanism analogous to that proposed by Jun et al.
for the corresponding intermolecular reaction. See ref 2f.
Vinyl ether 25 provides the most efficient reaction. At room
temperature, the reaction proceeded cleanly with ligand 16a, giving
JA0394986
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